Progranulin depletion inhibits proliferation via the transforming growth factor beta/SMAD family member 2 signaling axis in Kasumi-1 cells
Kuniaki Yabe,
Yasuko Yamamoto,
Masao Takemura,
Takeshi Hara,
Hisashi Tsurumi,
Ginette Serrero,
Toshitaka Nabeshima,
Kuniaki Saito
Affiliations
Kuniaki Yabe
Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan; A&T corporation, Kanagawa, Japan
Yasuko Yamamoto
Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan; Corresponding author.
Masao Takemura
Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan
Takeshi Hara
Department of Hematology, Matsunami General Hospital, Gifu, Japan
Hisashi Tsurumi
Department of Hematology, Matsunami General Hospital, Gifu, Japan
Ginette Serrero
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA; A&G Pharmaceutical, Inc., Columbia, MD, USA
Toshitaka Nabeshima
Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan
Kuniaki Saito
Department of Disease Control and Prevention, Fujita Health University Graduate School of Health Sciences, Aichi, Japan; Advanced Diagnostic System Research Laboratory, Fujita Health University, Graduate School of Health Sciences, Aichi, Japan; Japanese Drug Organization of Appropriate Use and Research, Nagoya, 468-0069, Japan; Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan
Progranulin is an autocrine growth factor that promotes proliferation, migration, invasion, and chemoresistance of various cancer cells. These mechanisms mainly depend on the protein kinase B (Akt)/mechanistic target of rapamycin (mTOR) pathway. Recent studies have shown that patients with hematopoietic cancer have elevated serum progranulin levels. Thus, the current study aimed to investigate the role of progranulin in hematopoietic cancer cells and how it modulates their proliferation. Both knockdown of progranulin and progranulin neutralizing antibody treatment inhibited proliferation in several human hematopoietic cancer cell lines. Moreover, progranulin depletion not only decreases the phosphorylation level of the Akt/mTOR pathway but also, surprisingly, increases the expression of transforming growth factor-beta (TGF-β) and phosphorylation of mothers against decapentaplegic homolog 2 (SMAD2) in Kasumi-1 cell. Furthermore, LY2109761, an inhibitor of TGF-β receptor type I/II kinase, and TGF-β neutralizing antibody blocked the inhibition of proliferation induced by progranulin depletion. These data provide new insights that progranulin alters cell proliferation via the TGF-β axis and progranulin could be a new therapeutic target for hematopoietic cancers.
